Question 8

College answer

Syllabus topic/section:

2.1.3 Sepsis and Infections / Antimicrobial use in ICU: L1
2.1.5 Respiratory Intensive Care / Pneumonia: L1

Discussion:  Part A: Virtually all of the candidates appreciated the value of the cycle time in distinguishing acute infection from delayed viral clearance. Most candidates did not clearly reject reinfection with COVID as a possibility. Reinfection within three weeks is very unlikely whereas prolonged viral shedding especially in the immunosuppressed is much more common and therefore difficult to determine whether active COVID infection is causing/ contributing to the current condition.
PART B: becoming familiar with the glossary of terms would have allowed more candidates to achieve a pass in this section. “Outline” requires more detail than a “List” question. An indication of early broad cover (ceftriaxone and azithromycin are not broad enough in the setting of immunosuppression) mentioning local microbiology resistance, dosage adjustments for a renal transplant and mentioning the use of oseltamivir would improve many candidates' answers.

Rationale in the answers was often missing or incomplete for example, stating “Voriconazole: fungal cover” is insufficient and attracted minimal marks. The better answer would justify the choice in terms of why it is superior to other agents, e.g. voriconazole: covers pulmonary aspergillosis better than echinocandins and less toxic to the transplant than amphotericin.
Part C: Candidates who prescribed steroids in underdosage, overdosage (unsafe practice) or did not provide dosages at all, lost marks as did those who ignored immunosuppressants such as tacrolimus and mycophenolate. A detailed knowledge of immunosuppressants was not required but demonstrating a familiarity with their presence in the ICU and how to approach management was required.
The complete answer contains these elements:
- Clarify usual regimen including doses.
- Liase with renal transplant team to balance risk of immunosuppression in sepsis vs transplant risk.
- Continue steroids at higher doses – equivalent to dexamethasone 6 mg for 10 days.
- Tacrolimus often continued; mycophenolate often held.
- Monitor serum levels tacrolimus and cyclosporin in conjunction with transplant team.

Discussion

This has ended up in the "Sepsis and infections" section because it felt like where a PCR-involving antibiotic- and immunosuppressant-heavy question should belong, as opposed to next to SAQs about mechanical ventilation and intubation.

a) Discuss your interpretation of the positive COVID PCR result.

What could this mean?

• Possinly ongoing infection: the patient is immunosuppressed and they often take longer to improve from COVID, potentially having a protracted course (Harris 2024)
• Possibly no longer infectious but still shedding viral RNA (in which case a high Ct count would help dismiss the idea that COVID is still the primary problem, as the Ct is proportionate to viral load). In which case this respiratory failure is something else entirely
• A reinfection within 3 weeks (i.e. a whole new COVID infection) is highly unlikely

a) Antimicrobial strategy, including rationale

Bilateral infiltrates in an immunocompromised patient? Oh god, what could this be. Fortunately the equation does not ask for one million differentials, but only the antibiotic strategy. That's easy: give all the things. But also:

• Consider renal clearance, wich may be sub-normal
• Take into account the fragility of the graft and try not to poison it with your amphotericin
• Read the history and assess what the patient is already colonised with (likely, after a renal transplant, they have seen a lot of hospital time, and must be covered in VRE and MRSA)
• Immunosuppressed patients are usually on PJP prophylaxis: this would be a good time to determine whether there was a gap in cover recently

Need to cover for:

• Gram +ve organisms, including MRSA (thus, vancomycin or tigecycline if one is worried about the graft)
• Gram -ve organisms, taking into account a long history of antibiotic  exposure (this, tazocin or meropenem)
• Intracellular pathogens (thus, IDSA guidelines also recommend a macrolide like azithromycin or a quinolone)
• Depending on how immunosuppressed and how much prophylaxis they have missed, Nocardia and PJP will be covered by TMP/SMX
• Fungal disease like aspergillosis cannot be ruled out, but is much less likely unless there is a long history of constant steroids. So, add voriconazole if there is a failure to respond to other agents (amphotericin would be too toxic to the transplant, and echinocandins are usually not effective),.
• Other viral illness, eg. influenza is also a differential, in which case this patient might benefit from oseltamivir

Thus, an answer with some rationale would have to include:

• Tazocin (renally adjusted)
• Vancomycin (renally adjusted and guided by serial levels)
• Azithromycin (no need to adjust)
• Oseltamivir (renally adjusted) until viral swab results become available
• If history is suspicious, eg. gaps in prophylaxis or long term steroids, add therapeutic trimethoprim-sulfamethoxazole and prednisone until PJP PCR is available
• If no improvement or suspicious radiology, add voriconazole (renally adjusted and guided by serial levels) until Aspergillus PCR is available
• If continuing COVID infection is supported by Ct values, and the patient is hypoxic, add dexamethasone
  • If the patient is showing features of a hyperinflammatory response (eg. raised CRP, raised ferritin, multiorgan system dysfunction), add baricitinib
  • If the respiratory failure is so severe that it required intibation or ECMO, add tocilizumab
• Lastly, consider noninfectious post-COVID organising pneumonia if none of the microbiology investigations are positive

b) What to do with the immunosuppressants

Unless some kind of Infinity Stones had suddenly wiped out all transplant physicians, no intensivist would ever undertake to unilaterally manage immunosuppression in a delicate situation such as this. As such, consultation is vital. The exam candidate should view the 2-mark allocation of this question as an indication that the college did not expect them to be transplant specialists, and therefore a part of the answer must surely have included some reference to things being done "in conjunction with transplant team". However, broad rules also exist:

• If COVID, then this is a viral disease for which there is a) an effective treatment and b) the need for immunomodulation anyway
• Thus, much of the immunosuppression can be continued, and corticosteroids may need to be escalated from the usual doses
• If this is another virus without a good effective treatment, then T-cell immunity becomes important, and the calcineurin inhibitors may need to be paused and steroids may need to be weaned while the rest of the therapy continues
• If this is a serious bacterial or opportunistic fungal infection, then strong innate immunity is key to success, and in this case steroids will need to be weaned as much as adrenal suppression permits, and antiproliferative agents (eg. mycophenolate, cyclosporine, cyclophosphamide, azathioprine) need to be withheld to permit the recovery of innate immune cells, while anti-T-cell agents such as tacrolimus may continue.
• If this is a condition that provokes a vigorous immune response with effective treatment or upon return of innate and humoral immunity (eg. TB meningitis), the steroids may need to be continued or even increased.
• Remember that a lot of these drugs are cleared by the transplanted organ, and measure their levels.

"A collaborative approach to decisionmaking with transplant physicians,  infectious diseases specialists and hospital pharmacists" is an example of a phrase one must include to appear to be a good citizen of the clinical professional community.